The present invention relates generally to closed loop control systems for administering a drug chemical to a subject, and more particularly to a control system for administering a drug wherein selected parameters of the control loop are dynamically varied in real time, responsive to the sensed physiological parameter(s) and the process reaction relationship thereby exercising optimally adaptive feedback control of drug administration.
Over the last two decades, it has become widely recognized that a dose of drug chemical does not, in itself, constitute safe and effective therapy in clinical usage. The manner in which the drug is administered to the body by drug-delivery systems can be equally important, if not more so. Therefore, drugs are marketed and employed not as pure chemical substances, but as drug products, which constitute drug-delivery systems.
Prior art drug-delivery systems have been broadly defined as chemical, mechanical, or electromechanical devices designed to input drugs to the systemic circulation or to specific target sites in the body at predetermined, controlled rates. If the drug input is not obtained at a predetermined controlled rate, however, the drug-delivery system can be best described as a drug-dump system. Most drug products currently on the market fall into the latter category in that the time course of their release (for example, via dissolution from a tablet) is generally fortuitous rather than being predetermined or designed on the basis of rational pharmacological criteria. The interested reader is referred to the article, "Bioavailability and Pharmacokinetic Analysis of Drug Responding Systems" (1978) by V. F. Smolen for an overview discussion of this subject. Despite extensive research and development efforts, very few chemical drug-delivery systems readily lend themselves to predetermined and controlled rates of drug release in vivo. In all cases, drug-release rates depend on the kinetic process of diffusion and/or on chemical reaction (hydrolysis), both of which are difficult to predict or control in a complex and often uncertain biologic environment within which the drug-delivery system must perform. Thus, controlled drug release is relatively difficult to attain by means of chemical systems, and up to the present time, such systems have been only partially successful.
Some drugs, such as intravenous anesthetics, hypotensive agents, and insulin, can require continuous readjustment of dose rates in response to the development of tolerances or hypersensitivities, or in accordance with changing patho-physiologic conditions or dietary factors. Such individualized dosage adjustment is especially important for rapidly acting drugs that have a narrow therapeutic range. What is needed to solve the problem of interpatient drug-response variability are closed loop drug products that release drugs to their physiologic sites of action in response to the patient's momentary therapeutic needs, rather than drug products that merely release quantities of drugs at standard rates that are predetermined by the product design and formulation.
Illustrative prior art devices of the closed loop type are disclosed in U.S. Pat. No. 2,690,178 to Bickford and in U.S. Pat. No. 4,080,966 to McNally et al. The Bickford '178 patent teaches the use of a proportional control circuit for the intermittent administration of drugs to maintain anesthesia, based on the decrease observed in the energy of the electroencephalographic (EEG) pattern with increasing depth of anesthesia. While this teaching represented a major advance in the art of controlled administrations of drugs, the actual implementation of the control system was somewhat primitive, and it was not widely accepted for practice in anesthesia. Also contributing to its limited acceptance was the increasing popularity of anesthetics other than ether and thiopental described in the disclosure; and the fact that the EEG patterns associated with these new drugs were not as directly related to anesthesia levels as was the pattern of ether and thiopental.
The McNally et al. '966 patent discloses an analog implemented closed loop control system used to regulate the blood pressure of mammals utilizing controlled infusion of drugs responsive to continuously monitored arterial blood pressure. The disclosed embodiment teaches the use of proportional plus derivative (plus integral) controlling techniques and recites the use of both liquid hypertensive agents, or liquid hypotensive agents into the circulatory system. Additional U.S. patents which disclose the use of closed loop techniques for administering medications of various kinds are U.S. Pat. No. 4,078,562 to Friedman; and U.S. Pat. No. 4,055,175 to Clemens et al. The Friedman patent discloses the use of periodically administering a pharmaceutical such as oxytocin or the like, to induce labor in a pregnant woman; while the Clemens et al patent describes an apparatus for controlling blood glucose by selected infusion of insulin and/or glucose responsive to a computer controlled output signal.
While a good deal of effort has been expended in the area of feedback drug administration, it is clear that a significant amount of work remains to be done, particularly with respect to the use of a wider range of drugs and in higher precision drug-delivery systems. Recent work resulting in the invention disclosed hereinbelow, has resulted in a system for automatic feedback-controlled administration of drugs (SAFCAD) for thiopental anesthesia that adapts to changes in patient responsiveness to the drug, thus maintaining an optimum controller action. A detailed description may be found in Cosgrove, R. J. and Smolen, V. F., "Systems for Automatic Feedback-Controlled Administration of Drugs: Analog and Digital Optimal-Adaptive Control of Thiopental Anesthesia," Innovations in Biomedicine, Proc. San Diego Biomedical Symposium, ed. Martin, J., North Hollywood, Calif., Western Periodicals, 1978. This SAFCAD for thiopental is considered useful not only for surgical anesthesia, but also for the treatment of cerebral ischemia resulting from brain injury, stroke and post-circulatory-arrest encephalopathy. In the latter group of conditions, long term infusion of a barbiturate such as thiopental may be necessary in comatose patients to minimize brain swelling. The mortality rate of head-injured patients undergoing barbiturate treatment in this manner was reported to be 35% of that associated with untreated head-injured patients. However, such barbiturate therapy requires meticulous patient monitoring, sometimes for several weeks or even longer. Use of a barbiturate SAFCAD could reduce the need for such monitoring, thereby rendering barbiturate therapy practical on a large scale. The present invention discloses precisely such a system.